Processes for preparing macrolides and ketolides and intermediates therefor

ABSTRACT

The invention described herein pertains to processes for the preparation of macrolide antibacterial agents. In particular, the invention pertains to processes for preparing macrolides and ketolides from erythromycin A.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application61/346,664, filed 20 May 2010, which is incorporated by referenceherein.

TECHNICAL FIELD

The invention described herein pertains to processes for the preparationof macrolide antibacterial agents. In particular, the invention pertainsto processes for preparing macrolides and ketolides from erythromycin A.

BACKGROUND AND SUMMARY OF THE INVENTION

Macrolide antibiotics, characterized by a large lactone ring to whichare attached one or more deoxy sugars, usually cladinose and desosamine,are antimicrobial drugs that are active against aerobic and anaerobicgram positive cocci and are prescribed for the treatment of respiratorytract and soft tissue infections. The macrolides, which belong to thepolyketide class of natural products, function by reversibly binding tothe 50S subunit of the bacterial ribosome, blocking protein synthesisand preventing bacterial growth and reproduction. Although this actionis primarily bacteriostatic, at higher concentrations, macrolides can bebactericidal. Erythromycin and the semi-synthetic derivativesazithromycin and clarithromycin are among the marketed macrolideantibiotics.

Ketolides, which are semi-synthetic derivatives of the 14-memberedmacrolide erythromycin A, belong to this class of drugs used to treatrespiratory tract infections. These drugs are effective againstmacrolide-resistant bacteria because of their ability to bind to twosites on the bacterial ribosome. Telithromycin and cethromycin belong tothis group of antibiotics.

Acquired bacterial resistance to macrolides occurs primarily throughpost-transcriptional methylation of the 23S bacterial ribosome. Thisresults in cross-resistance to macrolides, lincosamides andstreptogramins. Although rare, acquired resistance also can result fromthe production of drug-inactivating enzymes such as esterases orkinases, as well as the production of active ATP-dependent effluxproteins that transport macrolides out of the cell. A significantfraction of pneumococci are resistant to currently availableantibiotics. Accordingly, new macrolide and ketolide antibiotics areneeded, along with processes for preparing them.

In particular, international patent application publication No. WO2004/080391, and its counterpart publication US 2006/0100164, thedisclosures of which are incorporated herein by reference, describes afamily of macrolide and ketolide antibiotics, including fluoroketolideantibiotics, of formula (I)

and pharmaceutically acceptable salts thereof, wherein R¹⁰, X, Y, V, W,A, B, and C are as described herein, and Me indicates methyl, and Etindicates ethyl. One notable, but non-limiting example compound offormula (I) is solithromycin, also referred to as OP-1068 and/orCEM-101. The preparation of CEM-101 and related compounds is describedin WO 2009/055557, the disclosure of which is incorporated herein byreference. A starting material used in WO 2009/055557 A1 for thepreparation of the macrolide antibacterial agents is clarithromycin. Inthe processes described therein, clarithromycin is converted into aclarithromycin derivative in which the hydroxyl groups of the sugarmoieties are protected with acyl groups, such as clarithromycindibenzoate, also known as 2′,4″-di-O-benzoyl-6-O-methylerythromycin A,to form compounds of formula (II).

and pharmaceutically acceptable salts thereof, wherein R is as describedherein.

Clarithromycin is a semisynthetic antibacterial agent in which the6-hydroxy group of erythromycin A has been converted into a 6-methoxygroup to eliminate undesired interaction with the carbonyl group at the9-position of the macrolide ring, thereby stabilizing the antibiotic.Clarithromycin has been prepared by various processes. The most widelyused processes begin with erythromycin A, which is converted to itsoxime and then to a protected erythromycin A 9-oxime derivative as anintermediate, and variously involve protection and deprotection of thehydroxyl and dimethyl groups of the pendant sugar moieties before andafter methylation of the 6-hydroxy group of the macrolide ring (see, forexample, U.S. Pat. No. 6,515,116 for a review of the reported processes;an alternative approach including protection of the desosaminyl aminogroup as an N-oxide is described in U.S. Pat. No. 6,809,188). For theefficient production of a clarithromycin derivative in which thehydroxyl groups of the sugar moieties are protected with acyl groupsand, subsequently, of a final macrolide antibacterial agent, there isneeded a preparation of the diprotected derivative from erythromycin Awhich avoids the protecting and deprotecting steps used in the priormethodology for the preparation of clarithromycin. Described herein areprocesses for the direct production from erythromycin A ofclarithromycin derivatives of formula (II) in which the hydroxyl groupsof the sugar moieties are protected with acyl groups with a reducednumber of steps. Also described herein are processes for preparingcompounds of formula (I) from compounds of formula (II).

DETAILED DESCRIPTION

In one illustrative embodiment of the invention, processes are describedfor preparing compounds of formula (I)

and pharmaceutically acceptable salts thereof, wherein:

R¹⁰ is hydrogen, acyl or a prodrug moiety;

X is H; and Y is OR⁷; where R⁷ is monosaccharide, disaccharide, alkyl,arylalkyl, or heteroarylalkyl, each of which is optionally substituted,or acyl or C(O)NR⁸R⁹; where R⁸ and R⁹ are each independently selectedfrom the group consisting of hydrogen, hydroxy, alkyl, heteroalkyl,alkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of whichis optionally substituted, and dimethylaminoalkyl, acyl, sulfonyl,ureido, and carbamoyl; or R₈ and R₉ are taken together with the attachednitrogen to form an optionally substituted heterocycle; or X and Y aretaken together with the attached carbon to form carbonyl;

V is C(O), C(═NR¹¹), CH(NR¹², R¹³), or N(R¹⁴)CH₂; where N(R¹⁴) isattached to the C-10 carbon; where R¹¹ is hydroxy or alkoxy; R¹² and R¹³are each independently selected from the group consisting of hydrogen,hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl, each of which is optionally substituted, anddimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R¹⁴ ishydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl, each of which is optionally substituted,or dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl;

W is H, F, Cl, Br, I, or OH;

A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)₂NH, or C(O)NHS(O)₂;

B is (CH₂)_(n) where n is an integer from 0 to 10; or an unsaturatedcarbon chain of 2 to 10 carbons; and

C is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl, each of which is optionally substituted,or acyl, acyloxy, sulfonyl, ureido, or carbamoyl.

In another illustrative embodiment, processes are described forpreparing compounds of formula (II)

and pharmaceutically acceptable salts thereof, wherein R is an acylgroup. In another embodiment, R is a hindered acyl group, such asbenzoyl.

In another embodiment, processes are described herein comprising thestep of (a) contacting a compound of formula (III)

or an acid addition salt thereof, with an acylating agent to prepare acompound of formula (IV)

or an acid addition salt thereof; where in each instance Q incombination with the oxime oxygen forms an acetal or a ketal, or Q istropyl, and R is an acyl group. In another embodiment, the step (a) ofthe processes includes a base.

In another illustrative embodiment, processes are described hereincomprising the step of (b) contacting a compound of formula (IV), asdescribed herein, or an acid addition salt thereof, with a methylatingagent to prepare a compound of formula (V)

or an acid addition salt thereof, where Q and R are as described in thealternative embodiments herein. In another embodiment, the step (b) ofthe processes includes a base. In another embodiment, the step (b) ofthe processes includes an aprotic polar solvent.

In another illustrative embodiment, processes are described hereincomprising the step of (c) contacting a compound of formula (V), asdescribed herein, or an acid addition salt thereof, with a deoximatingagent to form the compound of formula (II),

or an acid addition salt thereof, where R is described in thealternative embodiments herein.

It is to be understood that each of the steps (a), (b), and (c) may becombined in additional embodiments. It is further to be understood thatthe variations of each of the steps (a), (b), and (c) described hereinmay be combined without limitation in additional embodiments. Forexample, another illustrative process comprises acylating step (a) andfurther comprises methylating step (b), and further comprisesdeoximating step (c). Another illustrative process comprises methylatingstep (b) and further comprises deoximating step (c). Anotherillustrative process comprises acylating step (a) and further comprisesmethylating step (b), and further comprises deoximating step (c), andfurther comprises steps described in WO 2009/055557 for convertingcompounds of formula (II) into compounds of formula (I).

In another embodiment, processes for preparing compounds of formula(IV), such as compounds of formula (IV) where R is benzoyl, or an acidaddition salt thereof, are described herein, where the processescomprise the step of contacting a compound of formula (III), asdescribed herein, or an acid addition salt thereof, with an acylatingagent, such as benzoyl anhydride, also referred to as benzoic anhydride,to form a compound of formula (IV), or an acid addition salt thereof. Inone variation, the step is performed in the presence of a base.

In another embodiment, processes for preparing compounds of formula (V),or an acid addition salt thereof, as described herein, where theprocesses comprise the step of contacting a compound of formula (IV), asdescribed herein, or an acid addition salt thereof, with a methylatingagent, to form a 6-O-methyl compound of formula (V), as describedherein, or an acid addition salt thereof. In one variation, the step isperformed in the presence of a base. In another variation, the step isperformed in an aprotic polar solvent. In another variation, the step isperformed in the presence of a base and in an aprotic polar solvent.

In another embodiment, processes for preparing compounds of formula(II), including compounds of formula (II) where R is benzoyl, or an acidaddition salt of any of the foregoing, are described herein, where theprocesses comprise the step of contacting a compound of formula (V), asdescribed herein, or an acid addition salt thereof, with a deoximatingagent to form a compound of formula (II), or an acid addition saltthereof.

In another illustrative embodiment of any of the foregoing processes, Qis an O-protecting group. In one variation, Q in combination with theoxime oxygen forms an acetal or ketal, or Q is tropyl. In anotherillustrative embodiment, R is an acyl group. In another illustrativeembodiment, Q is an O-protecting group. In one variation, Q incombination with the oxime oxygen forms an acetal or ketal, or Q istropyl, and R is an acyl group.

In another illustrative embodiment of any of the foregoing processes, Qis C(R^(A))(R^(C))(OR^(B)), wherein

R^(A) is a group of the formula CH₂R^(D), where R^(D) is hydrogen,(1-3C)alkyl or (1-6C)alkoxy;

R^(B) is (1-6C)alkyl, (5-7C)cycloalkyl; phenyl or arylalkyl; and

R^(C) is hydrogen, (1-4C)alkyl, phenyl or arylalkyl; or alternatively inany of the foregoing

R^(B) and R^(D) together form an ethylene, propylene or trimethylenegroup; or

R^(B) and R^(D) together form a (3-5C)alkanediyl group which may befurther substituted with one to three (1-3C)alkyl substituents; or

R^(B) and R^(C) together form a (3-4C)alkanediyl group.

In another embodiment of any of the foregoing processes, Q is2-methoxy-2-propyl, 1-methoxycyclohexyl, or 1-isopropoxycyclohexyl. Inanother embodiment of any of the foregoing processes, Q is2-methoxy-2-propyl.

Compounds of formula (III), as described herein, may be prepared bycontacting erythromycin A 9-oxime with a corresponding compound offormula R^(E)—C(R^(A))(R^(C))(OR^(B)) in which R^(E) is (1-6C)alkoxy orin which R^(A) and R^(E) together form a group of formula CHRD connectedby a double bond. The step may be carried out in the presence of anacidic catalyst, for example in the presence of pyridine hydrochloride.In another variation, the step is performed using 2-methoxypropene toform a compound of formula (III) in which Q is 2-methoxy-2-propyl. Inanother variation, the step is performed, in dichloromethane at about 0°C. to about room temperature in the presence of pyridine hydrochlorideusing excess 2-methoxypropene. In another variation, Q is tropyl, andthe compounds of formula (III) may be prepared by reacting erythromycinA 9-oxime with tropylium tetrafluoroborate in an aprotic polar solvent.

In another embodiment of any of the processes described herein, R is asterically hindered acyl group, such as a benzoyl group. In anotherembodiment of any of the processes described herein, R is not acetyl.Without being bound by theory, it is believed herein that the use of asterically hindered group R may improve the processes and/or the purityof the isolated product of the processes. It has been discovered thatunhindered acyl groups, such as acetyl groups, present on the C-5saccharide may migrate to other positions on the macrolide, for examplefrom the 2′-hydroxy group of the desosamine moiety to an amino group ofa side chain. Use of a sterically hindered group R decreases and/orprecludes such a migration leading to improved processes and/or improvedpurities of the isolated product of the processes

In another embodiment of any of the processes described herein, R isbenzoyl.

In another embodiment of any of the processes described herein, step (a)is performed with an acylating agent is the anhydride, acid halide, oran activated ester of the corresponding acyl group R. In anotherembodiment of any of the processes described herein, the acylating agentis the anhydride of the acyl group R. In another embodiment of any ofthe processes described herein, about 2 to about 6 equivalents ofacylating agent to an equivalent of the compound of formula (III) isemployed. In another embodiment of any of the processes describedherein, a base is included in step (a), such as a tertiary amine. Inanother embodiment of any of the processes described herein, the base istriethylamine, diisopropylethylamine, or 4-methylmorpholine, or acombination thereof. In another embodiment of any of the processesdescribed herein, about 1 to about 4 equivalents of base to anequivalent of the compound of formula of formula (III) is employed. Inanother embodiment of any of the processes described herein, theacylation is performed in the presence of about 0.5 to about 2.5equivalents of an acylation catalyst to an equivalent of the compound offormula of formula (III). In another embodiment of any of the processesdescribed herein, the acylation catalyst is 4-dimethylaminopyridine.

In another embodiment of any of the processes described herein, themethylating agent is methyl bromide, methyl iodide, dimethyl sulfate,methyl p-toluenesulfonate, or methyl methanesulfonate. In anotherembodiment, the methylating agent is methyl iodide. In anotherembodiment of a process described herein, a base is used in combinationwith the methylating agent, such as sodium hydroxide, potassiumhydroxide, sodium hydride, potassium hydride, or potassium t-butoxide,or a mixture thereof. In another embodiment the base used with themethylating agent is potassium hydroxide. In another embodiment themethylation step is performed in an aprotic polar solvent, such asdimethyl sulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, a mixturethereof, or a mixture of any of these solvents with one or more oftetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane,acetonitrile or ethyl acetate. In another embodiment of any of theprocesses described herein, the methylating step is performed at atemperature from about −15° C. to about 60° C. Another embodiment ofprocesses described herein for the methylation of a compound of formula(IV) is one wherein the methylating step is performed at a temperaturefrom about 0° C. to about 30° C.

It has been unexpectedly discovered herein that the methylation step ofcompounds of formula (IV), where R is benzoyl, is performed without, anyor substantially any, cleavage of the benzoate ester present oncompounds of formula (IV).

Illustratively, removal of the group Q, such as by 0-deprotection,and/or removal of the oxime group at C-9 to form a ketone, such as bydeoximation, may be performed using any of a number of conventionalprocesses and/or reagents. Illustrative deoximation methods include, butare not limited to, hydrolytic, oxidative and reductive conditions. Inone embodiment, the deoximating agent comprises a reducing agent.Illustrative embodiments of deoximating agents include, but are notlimited to, inorganic sulfur oxide compounds such as sodium hydrogensulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodiumhydro sulfite, sodium metabisulfite, sodium bisulfite, sodiumdithionate, potassium hydrogen sulfite, potassium thiosulfate andpotassium metabisulfite, and mixtures thereof. In another embodiment ofany of the processes described herein, the deoximating agent is sodiummetabisulfite or sodium bisulfite, or a combination thereof. It is to beunderstood that 0-deprotection may be performed prior to deoximation; orO-deprotection and deoximation may be performed in a single (“one-pot”)step by treatment, either sequentially, concurrently, contemporaneously,or simultaneously by using acid, such as formic acid, and a deoximatingagent.

In another embodiment of any of the processes described herein, the stepof converting the C-9 oxime into a carbonyl is performed by contactingthe compound of formula (V) wherein the deoximating agent comprisesformic acid and sodium metabisulfite in an aqueous alcoholic solution ata temperature ranging from ambient temperature to about the boilingpoint of the solvent.

It has been unexpectedly discovered that removing the 0-protecting groupQ and removing the oxime from a compound of formula (V) in which R isbenzoyl may be performed without, any or substantially any, cleavage ofthe benzoate ester present on compounds of formula (V).

It is to be understood that the various subgenera, species, andcompounds described herein may be made by the various embodiments of theprocesses described herein. For example, in another embodiment of any ofthe processes herein, V is C(O); and/or

R⁷ is an aminosugar or a halosugar; or

R⁷ is 4-nitro-phenylacetyl or 2-pyridylacetyl; or

X and Y are taken together with the attached carbon to form carbonyl;and/or

A is CH₂; and/or

B is alkenylene; and/or

B is (CH₂)_(n); where n is 2 to 6, 2 to 5, or 2 to 4, or 2 to 3, or 3;and/or

C is aminophenyl; or

C is 3-aminophenyl; and/or

W is fluoro; or

W is hydrogen; and/or

R¹⁰ is hydrogen or acyl; or

R¹⁰ is hydrogen; or

R¹⁰ is benzoyl.

In another embodiment of any of the processes described herein, thecompound of formula (I) is CEM-101, or a pharmaceutically acceptablesalt, solvate or hydrate thereof. The compound CEM-101 has ChemicalAbstracts Registry Number 760981-83-7, and structure of the compound isas follows:

As used herein, the term “alkyl”, alone or in combination, refers to anoptionally substituted straight-chain, optionally substitutedbranched-chain, or optionally substituted cyclic alkyl radical havingfrom 1 to about 30 carbons, more preferably 1 to 12 carbons. Examples ofalkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyland the like. A “lower alkyl” is a shorter alkyl, e.g., one containingfrom 1 to about 6 carbon atoms.

The term “alkoxy,” alone or in combination, refers to an alkyl etherradical, alkyl-O, wherein the term alkyl is defined as above. Examplesof alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “alkenyl,” alone or in combination, refers to an optionallysubstituted straight-chain, optionally substituted branched-chain, oroptionally substituted cyclic alkenyl hydrocarbon radical having one ormore carbon-carbon double-bonds and having from 2 to about 30 carbonatoms, more preferably 2 to about 18 carbons. Examples of alkenylradicals include ethenyl, propenyl, butenyl, 1,4-butadienyl and thelike. The term can also embrace cyclic alkenyl structures. A “lowerakenyl” refers to an alkenyl having from 2 to about 6 carbons.

The term “acyloxy” refers to the ester group OC(O)—R, where R is H,alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein the alkyl, alkenyl,alkynyl and arylalkyl groups may be optionally substituted.

The term “acyl” includes alkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl substituents attached to a compound via a carbonylfunctionality (e.g., CO-alkyl, CO-aryl, CO-arylalkyl orCO-heteroarylalkyl, etc.).

The term “heteroalkyl” generally refers to a chain of atoms thatincludes both carbon and at least one heteroatom. Illustrativeheteroatoms include nitrogen, oxygen, and sulfur.

As used herein, the term “aryl” includes monocyclic and polycyclicaromatic carbocyclic and aromatic heterocyclic groups, each of which maybe optionally substituted. As used herein, the term “heteroaryl”includes aromatic heterocyclic groups, each of which may be optionallysubstituted. Illustrative carbocyclic aromatic groups described hereininclude, but are not limited to, phenyl, naphthyl, and the like.Illustrative heterocyclic aromatic groups include, but are not limitedto, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,benzisoxazolyl, benzisothiazolyl, and the like.

The term “arylalkyl” refers to an alkyl group substituted with one ormore unsubstituted or substituted monocyclic or polycyclic aryl groups.Illustrative arylalkyl groups include benzyl, diphenylmethyl, trityl,2-phenylethyl, 1-phenylethyl, 2-pyridylmethyl, 4,4′-dimethoxytrityl, andthe like.

The term “alkylaryl” refers to an aryl group substituted with an alkylgroup.

The term “sulfonyl” refers to SO₂—R where R is H, alkyl or aryl.

The term “saccharide” includes monosaccharides, disaccharides, andpolysaccharides, each of which is optionally substituted. The term alsoincludes sugars and deoxysugars optionally substituted with amino,amido, ureyl, halogen, nitrile, or azido groups. Illustrative examplesinclude, glucosamine, N-acetylglucosamine, desos amine, forosamine,sialic acid, and the like.

The term “activated ester” includes carboxylic acid derivatives in whichthe hydrogen of the hydroxy group has been replaced with a residue whichresults in the formation of a good leaving group, including the4-nitrophenyl ester and an activated ester or anhydride derived from acoupling reagent.

In another embodiment, compounds of formula (IV) are described

and acid addition salts thereof; wherein Q and R are as described in thevarious embodiments herein.

In another embodiment, compounds of formula (V) are described

and acid addition salts thereof; wherein Q and R are as described in thevarious embodiments herein.

It is appreciated herein that because compounds of formulae (I), (II),(III), (IV), and (V) each contain a dimethylamino group on thedesosaminyl moiety, the compounds may form acid addition salts.Accordingly, it is to be understood that any acid addition salt of acompound of formulae (I), (II), (III), (IV), and (V) suitable for use inpharmaceutical manufacturing or for providing a free base which issuitable for use in pharmaceutical manufacturing is described herein andto be included in the invention described herein.

In each of the foregoing and following embodiments, it is to beunderstood that the formulae include and represent not only allpharmaceutically acceptable salts of the compounds, but also include anyand all hydrates and/or solvates of the compound formulae. It isappreciated that certain functional groups, such as the hydroxy, amino,and like groups form complexes and/or coordination compounds with waterand/or various solvents, in the various physical forms of the compounds.Accordingly, the above formulae are to be understood to include andrepresent those various hydrates and/or solvates. In each of theforegoing and following embodiments, it is also to be understood thatthe formulae include and represent each possible isomer, such asstereoisomers and geometric isomers, both individually and in any andall possible mixtures. In each of the foregoing and followingembodiments, it is also to be understood that the formulae include andrepresent any and all crystalline forms, partially crystalline forms,and non crystalline and/or amorphous forms of the compounds. Forexample, Illustrative crystal morphologies are described in co-pendingPCT international application No. PCT/US2011/029424, the disclosure ofwhich is incorporated herein in its entirety.

EXAMPLES

The following examples further illustrate specific embodiments of theinvention; however, the following illustrative examples should not beinterpreted in any way to limit the invention. Abbreviations used in theexamples include the following: DCM, dichloromethane; DMAP,4-dimethylaminopyridine; DMSO; dimethyl sulfoxide; EA, ethyl acetate;¹H-NMR, proton nuclear magnetic resonance spectroscopy; MeOH, methanol;Mw, molecular weight; RT, room (ambient) temperature; THF,tetrahydrofuran; TLC, thin layer chromatography.

EXAMPLE. Synthesis of erythromycin A 9-oxime (1). A mixture oferythromycin A (15 g, 20.4 mmol), NH₂OH.HCl (7.3 g, 105 mmol) andtriethylamine (7 g, 69 mmol) in MeOH (23 mL) is heated to refluxovernight. A white solid forms during the reaction. The reaction mixtureis concentrated to a small volume. To the obtained residue is addeddilute aqueous NH₄OH solution at 0° C. until the pH of the mixturereaches about 10 to 11. Additional solid precipitates out from themixture. The mixture is filtered, the collected solid is washed withwater and dried under vacuum to give 14.2 g of 1 as white granular solidin 93% yield. TLC analysis (DCM:MeOH:NH₄OH=90:10:1) of the obtained 1shows a small amount of an additional compound (lower spot),corresponding to the Z-isomer. Mass analysis of the obtained 1 showed apeak with Mw=749, corresponding to the title compound. ¹H-NMR analysisof the product is consistent with the title compound, and also shows amixture of the (1) and the HCl salt thereof. The product is used withoutpurification.

EXAMPLE. Large Scale Preparation of (1). Erythromycin (250 g, 0.34 mol)and hydroxylamine hydrochloride (80.3 g, 1.15 mol) in methanol (325 ml)are heated under reflux in the presence of triethylamine (45 g, 0.44mol). The reaction is monitored by TLC using toluene/triethylamine (8:2)as eluent. After completion (ca. 24 h), the reaction mass is graduallycooled and stirred at 0-5° C. for 1 h, filtered and washed with cooledmethanol (100 mL). The wet solid (265 g) is suspended in isopropylalcohol (350 mL) and heated to 50-55° C. followed by the addition ofaqueous ammonia (650 mL) over a period of 2 h. The solution is stirredfor 1 h at 50-55° C. and gradually cooled to 10-15° C. and maintainedfor 2 h. The solid was filtered and washed with water and dried at80-85° C. for 12 h to isolate 186 g. About 3% of the correspondingZ-oxime isomer is observed by HPLC. The preparation is repeated asfollows with the corresponding scale of other reagents.

No. Batch Size Product Yield (%) Purity by HPLC 1 100 g  73 g 74% 93% +3% of Z-oxime 2 250 g 186 g 73% 95% + 3% of Z-oxime 3 250 g 187 g 73%95% + 3% of Z-oxime

EXAMPLE. Synthesis of a Compound of Formula (III), Q=2-methoxy-2-propyl(9). To a solution of (1) (3 g, 4 mmol) in anhydrous dichloromethane(DCM, 21 mL) is added 2-methoxypropene (1.5 g, 20.8 mmol), followed bypyridine hydrochloride (0.72 g, 6.2 mmol) at 0° C. After the addition,the reaction mixture is stirred at 0° C. at RT for 30 min. Conversion ismonitored by TLC analysis of the reaction mixture(DCM:MeOH:NH₄OH=90:10:1). If conversion is incomplete, the mixture iscooled back to 0° C., and another 0.5 g of 2-methoxypropene (6.9 mmol)is added. The mixture is stirred at 0° C. for another 0.5 h. Ifconversion is incomplete, another 0.5 g of 2-methoxypropene (6.9 mmol),followed with another 0.1 g of pyridine hydrochloride (0.86 mmol) isadded to the reaction mixture at 0° C. The reaction mixture was stirredat 0° C. for another 15 min. Upon complete conversion, the reactionmixture is diluted with saturated aqueous NaHCO₃ solution. The DCM layeris separated and the aqueous layer is extracted with DCM. The combinedDCM layers are washed with brine, dried over MgSO₄, concentrated todryness to give 3.3 g crude product as a white foam in quantitativeyield. Mass analysis of the product shows Mw=821, corresponding to thetitle compound, and a very minor peak with molecular weight of 861.¹H-NMR of the product is consistent with the title compound, and a smallamount 2-methoxypropan-2-ol and pyridine. The product is used withoutfurther purification.

EXAMPLE. Synthesis of a Compound of Formula (IV), Q=2-methoxy-2-propyl,R=benzoyl (10). To a solution of (9) (4.1 g, 5 mmol) in ethyl acetate(65 mL) is added benzoyl anhydride (4.5 g, 20 mmol), followed bytriethylamine (1.26 g, 12.5 mmol) and DMAP (0.9 g, 7.4 mmol) at RT. Theresulting mixture is stirred at RT for 36 h. The reaction mixture isdiluted with saturated aqueous NaHCO₃ solution. The EA layer isseparated and the aqueous layer is extracted with EA. The combined EAlayers are washed with brine, dried over MgSO₄, filtered to remove thedrying agent, and concentrated to dryness. The obtained residue issubjected to silica gel column chromatography (DCM:MeOH:NH₄OH=97:3:0.3)to give 4.2 g of 10 in 80% yield as a white solid. Mass analysis of thepurified product shows Mw=1029, corresponding to the title compound.¹H-NMR is consistent with the title compound.

EXAMPLE. Large Scale Preparation of (9). Erythromycin Oxime (1) (200 g,026 mol) is dissolved in DCM (1.4 L) and the volume is reduced to 1 L bydistillation under atmospheric pressure. After cooling the reaction massto 0-5° C., 2-methoxypropene (80 g, 1.1 mol) and pyridine hydrobromide(50 g, 0.31 mol) are added and stirred for 3 h at 20-25° C. Massanalysis confirmed the presence of (9). Without isolation, benzoicanhydride (211 g, 0.93 mol), triethylamine (54 g, 0.53 mol), DMAP (48.8g, 0.40 mol) are added and the reaction is continued for 24 h at 30° C.The reaction is monitored by TLC and analyzed by mass spectrometry.After completion, saturated sodium bicarbonate (1 L) is added andstirred for 15 min and allowed to settle. The layers are separated andthe organic layer is concentrated. The material is isolated to 190 gwith a purity of 48-51%. The preparation is repeated as follows with thecorresponding scale of other reagents.

Unpurified No. Batch Size Product Purity 1 200 g 190 g 48% 2 200 g 186 g50% 3 200 g 184 g 51%

The unpurified product from successive batches is combined (450 g) anddissolved in EA (4.5 L) to a clear solution that is washed withsaturated sodium bicarbonate (2.2 L), water (2.2 L), and brine (2.2 L),and concentrated. The isolated product is crystallized from IPE/n-Hexaneto 360 g (84%).

EXAMPLE. Synthesis of a Compound of Formula (V), Q=2-methoxy-2-propyl,R=benzoyl (11). A solution of (10) (3.8 g, 3.7 mmol) in anhydrous THF(15 mL) and anhydrous DMSO (15 mL) is cooled to 0° C. Powdered KOH (0.46g, 8.2 mmol) is added, followed by methyl iodide (1.06 g, 7.5 mmol) at0° C. The resulting reaction mixture is stirred at 0° C. for 5 min,subsequently becoming a thick paste and stopping the stirring. Themixture is warmed to RT for 5 min, remaining a thick paste, and dilutedwith 15 mL of THF and 15 mL of DMSO, to a free flowing suspension. Themixture is stirred at RT for another 0.5 hr, diluted with saturatedaqueous NaHCO₃ solution, and extracted with ethyl acetate. The ethylacetate extract is washed with brine, dried over MgSO₄ and concentratedto dryness. The isolated residue is purified by silica gel columnchromatography (DCM:MeOH:NH₄OH=97:3:0.3) to 2.83 g of (11) as a whitesolid in 73% yield. Mass analysis shows Mw=1043), corresponding to thetitle compound, along with a minor peak Mw=1057. ¹H-NMR is consistentwith the title compound.

EXAMPLE. Large Scale Preparation of (11). Benzoylated oxime (10) (100 g,0.09 mol) is dissolved in toluene (1.8 L) and the solution is distilledunder vacuum to remove toluene (300 mL), cooled to 15° C., and dilutedwith DMSO (1.5 L). After cooling to 5° C., methyl iodide (20.5 g, 0.14mol) is added followed by KOH (10.8 g, 0.19 mol) and the reaction iscontinued for 3 h. The reaction is stopped by the addition of 40%dimethylamine (22 g) and the temperature of the reaction mass is raisedto RT and diluted with water (500 mL) with stirring. The layers areseparated and the aqueous layer is extracted with toluene (500 mL). Thecombined organic layers are washed with water (2 L) and the organiclayer is concentrated by distillation under vacuum. The isolated productis stirred in IPE (500 mL) for 5 h and filtered to 82 g of the titlecompound, which is used without further purification. The preparation isrepeated as follows with the corresponding scale of other reagents.

No. Batch Size Product Yield (%) 1 100 g 82 g — 2 100 g 78 g — 3 100 g84 g — 4  90 g 71 g 80%

EXAMPLE. Synthesis of a Clarithromycin Dibenzoate, Formula (II),R=benzoyl. To a solution of (11) (800 mg, 0.78 mmol) in ethanol (8 mL)and water (8 mL) is added sodium metabisulfite (740 mg, 3.89 mmol) atRT. The resulting mixture is adjusted to pH 2-3 by adding formic acid(1.5 mL). The mixture is heated at 60° C. for 1 h. Conversion ismonitored by mass spectrometry. If incomplete, or showing a large amountof the deprotected oxime intermediate (Mw=971), another 2 g of sodiummetabisulfite (10.5 mmol) is added. The mixture is stirred at 60° C. foranother 7 h, then cooled to RT. A white solid precipitate forms as thereaction progresses. The reaction mixture is neutralized with diluteaqueous NaHCO₃ solution to pH of 8-9 and the resulting mixture isfiltered. The isolated white solid is dried under vacuum to 760 mg ofclarithromycin dibenzoate. The unpurified product is combined withmaterial obtained from other preparations (ca. 200 mg) and purified bysilica gel column chromatography to 730 mg of clarithromycin dibenzoatein 79% yield. Mass analysis shows Mw=956, corresponding to the titlecompound, with a minor peak of Mw=970, which is attributed to thecarryover impurity in (11). ¹H-NMR is consistent with the titlecompound.

EXAMPLE. Large Scale Preparation of Clarithromycin Dibenzoate.Methylated oxime (11) (80 g, 0.07 mol) is dissolved in absolute alcohol(400 mL). Water (400 mL) is added, followed by sodium bisulfite (72 g,0.69 mol) and formic acid (21 g). The reaction mass is heated to refluxfor 6 h, cooled to RT, and diluted with water (400 mL). The reactionmass is cooled to 10-15° C., and 25% NaOH (160 ml) is added slowly. Themixture is stirred for 2 h and filtered. The isolated solid is washedwith water (500 mL) and dissolved in ethylacetate (400 mL). The organiclayer is washed with water (400 mL), then brine (400 mL), thenconcentrated. The isolated material is crystallized from ethyl acetate(1.7 T) to 40.8 g (95% purity). Alternatively, the isolated material iscrystallized from IPA/IPE 89-90% purity. The preparation is repeated asfollows with the corresponding scale of other reagents.

No. Batch Size Product Yield (%) 1 80 g 40.8 g 95% 2 70 g 37.8 g 90% 370 g   45 g 89%

What is claimed is:
 1. A process for preparing a compound of formula(I),

or a pharmaceutically acceptable salt thereof, wherein: R¹⁰ is hydrogen,acyl or a prodrug moiety; X is H; and Y is OR⁷; where R⁷ ismonosaccharide, disaccharide, alkyl, arylalkyl, or heteroarylalkyl, eachof which is optionally substituted, or acyl or C(O)NR⁸R⁹; where R⁸ andR⁹ are each independently selected from the group consisting ofhydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, aryl, arylalkyl,heteroaryl, and heteroarylalkyl, each of which is optionallysubstituted, and dimethylaminoalkyl, acyl, sulfonyl, ureido, andcarbamoyl; or R₈ and R₉ are taken together with the attached nitrogen toform an optionally substituted heterocycle; or X and Y are takentogether with the attached carbon to form carbonyl; V is C(O), C(═NR¹¹),CH(NR¹², R¹³), or N(R¹⁴)CH₂; where N(R¹⁴) is attached to the C-10carbon; where R¹¹ is hydroxy or alkoxy; R¹² and R¹³ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl, each of which is optionally substituted, anddimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R¹⁴ ishydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl, each of which is optionally substituted,or dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl; W is H, F,Cl, Br, I, or OH; A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)₂NH, orC(O)NHS(O)₂; B is (CH₂)_(n) where n is an integer from 0 to 10; or anunsaturated carbon chain of 2 to 10 carbons; and C is hydrogen, hydroxy,alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl, each of which is optionally substituted, or acyl,acyloxy, sulfonyl, ureido, or carbamoyl; the process comprising (a) thestep of contacting a compound of formula (III),

or an acid addition salt thereof, wherein Q in combination with theoxime oxygen forms an acetal or ketal, or Q is tropyl, with an acylatingagent to form a compound of formula (IV)

or an acid addition salt thereof, wherein R is an acyl group; or theprocess comprising (b) the step of contacting a compound of formula(IV), or an acid addition salt thereof, with a methylating agent, toform a compound of formula (V)

or an acid addition salt thereof; or the process comprising (c) the stepof contacting a compound of formula (V), or an acid addition saltthereof, with a deoximating agent to form a compound of formula (II)

or an acid addition salt thereof; or the process comprising anycombination of (a), (b), and (c).
 2. The process of claim 1 comprising(a) and (b).
 3. The process of claim 1 comprising (a) and (c).
 4. Theprocess of claim 1 comprising (b) and (c).
 5. The process of claim 1comprising (a), (b), and (c).
 6. The process of any one of claims 1 to 5wherein step (a) is performed in the presence of a base.
 7. The processof any one of claims 1 to 5 wherein step (b) is performed in thepresence of a base.
 8. The process of any one of claims 1 to 5 whereinstep (b) is performed in an aprotic polar solvent.
 9. The process of anyone of claims 1 to 5 wherein V is C(O).
 10. The process of any one ofclaims 1 to 5 wherein W is fluoro.
 11. The process of any one of claims1 to 5 wherein W is hydrogen.
 12. The process of any one of claims 1 to5 wherein X and Y are taken together with the attached carbon to formcarbonyl.
 13. The process of any one of claims 1 to 5 wherein A is CH₂.14. The process of any one of claims 1 to 5 wherein B is alkenylene. 15.The process of any one of claims 1 to 5 wherein B is (CH₂)_(n), where nis an integer from 2 to
 4. 16. The process of any one of claims 1 to 5wherein C is 3-aminophenyl.
 17. The process of any one of claims 1 to 5wherein R¹⁰ is benzoyl.
 18. The process of any one of claims 1 to 5wherein R is hydrogen.
 19. The process of any one of claims 1 to 5wherein the compound of formula (I) is of the formula

or a pharmaceutically acceptable salt thereof.
 20. A process forpreparing a compound of formula (II);

or a pharmaceutically acceptable salt thereof, wherein: R is an acylgroup; the process comprising (a) the step of contacting a compound offormula (III),

or an acid addition salt thereof, wherein Q in combination with theoxime oxygen forms an acetal or ketal, or Q is tropyl, with an acylatingagent to form a compound of formula (IV)

or an acid addition salt thereof, wherein R is an acyl group; or theprocess comprising (b) the step of contacting a compound of formula(IV), or an acid addition salt thereof, with a methylating agent, toform a compound of formula (V)

or an acid addition salt thereof; or the process comprising (c) the stepof contacting a compound of formula (V), or an acid addition saltthereof, with a deoximating agent to form a compound of formula (II); orthe process comprising any combination of (a), (b), and (c).
 21. Theprocess of claim 20 comprising (a) and (b).
 22. The process of claim 20comprising (a) and (c).
 23. The process of claim 20 comprising (b) and(c).
 24. The process of claim 20 comprising (a), (b), and (c).
 25. Theprocess of any one of claims 20 to 24 wherein step (a) is performed inthe presence of a base.
 26. The process of any one of claims 20 to 24wherein step (b) is performed in the presence of a base.
 27. The processof any one of claims 20 to 24 wherein step (b) is performed in anaprotic polar solvent.
 28. A compound of formula (IV)

or an acid addition salt thereof, wherein Q in combination with theoxime oxygen forms an acetal or ketal, or Q is tropyl, and R is an acylgroup.
 29. A compound of formula (V)

or an acid addition salt thereof, wherein Q in combination with theoxime oxygen forms an acetal or ketal, or Q is tropyl, and R is an acylgroup.
 30. The process or compound of any one of claims 1 to 5, 20 to24, or 28 to 29 wherein Q is 2-methoxy-2-propyl, 1-methoxycyclohexyl or1-isopropoxycyclohexyl.
 31. The process or compound of any one of claims1 to 5, 20 to 24, or 28 to 29 wherein Q is 2-methoxy-2-propyl.
 32. Theprocess or compound of any one of claims 1 to 5, 20 to 24, or 28 to 29wherein R is a sterically hindered acyl group.
 33. The process orcompound of any one of claims 1 to 5, 20 to 24, or 28 to 29 wherein R isbenzoyl.
 34. The process of any one of claims 1 to 5 or 20 to 24 whereinthe acylating agent is the anhydride.
 35. The process of any one ofclaims 1 to 5 or 20 to 24 wherein the base in step (a) is a tertiaryamine.
 36. The process of any one of claims 1 to 5 or 20 to 24 whereinstep (a) is performed in the presence of 4-dimethylaminopyridine. 37.The process of any one of claims 1 to 5 or 20 to 24 wherein themethylating agent in step (b) is methyl bromide, methyl iodide, dimethylsulfate, methyl p-toluenesulfonate or methyl methanesulfonate.
 38. Theprocess of any one of claims 1 to 5 or 20 to 24 wherein the base in step(b) is sodium hydroxide, potassium hydroxide, sodium hydride, potassiumhydride or potassium t-butoxide or a mixture thereof.
 39. The process ofany one of claims 1 to 5 or 20 to 24 wherein the aprotic polar solventin step (b) is dimethyl sulfoxide, dimethylformamide,1-methyl-2-pyrrolidone, a mixture thereof, optionally further forming amixture with one or more of tetrahydrofuran, 2-methyltetrahydrofuran,1,2-dimethoxyethane, acetonitrile, or ethyl acetate.
 40. The process ofany one of claims 1 to 5 or 20 to 24 wherein the deoximating agent instep (c) comprises a reducing agent.
 41. The process of any one ofclaims 1 to 5 or 20 to 24 wherein the deoximating agent in step (c)comprises formic acid and sodium metabisulfite.